Abdulfatah, Eman

Abstract Introduction: Atypical hyperplasia (also known as proliferative disease with atypia), while categorized as a benign finding, has been consistently associated with an increased risk of subsequent breast cancer that persists for decades after initial diagnosis. There are various other lesions that are classified as benign breast disease (BBD) that are routinely identified by pathologists that may also increase risk and be of use to inform breast cancer risk models. We sought to identify which BBD lesions were associated with increased risk of breast cancer in an African American (AA) cohort. Methods: Benign breast biopsies from 3,895 AA women diagnosed with BBD between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including columnar alterations, ductal ectasia, ductal hyperplasia, fibrosis, apocrine metaplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and fibroadenomas. Women were followed for subsequent breast cancer using the Metropolitan Detroit Cancer Surveillance System, part of the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between BBD features and subsequent breast cancer were examined using chi-square tests. Features that had a significant chi-square test result were also combined into scores describing the overall number of BBD features identified, termed busy breast score. Multivariable log-binomial regression with backward selection based on BIC criteria was performed to assess risk ratio and 95% confidence intervals of breast cancer on 12 candidate features. Multivariable log-binomial regression was performed for busy breast score as well. All regression models were adjusted for age at biopsy and overall impression for presence of proliferative disease with or without atypia using non-proliferative disease as the reference. Models were checked for multicollinearity using a variable inflation factor (VIF). Results: Of the 3,895 AA women in the BBD cohort, 210 developed a subsequent breast cancer. The median age at biopsy among those without a subsequent cancer (controls) was 47 years of age, while cases were 53 years of age (p-value<0.001). In univariate analyses, ductal hyperplasia (p-value=0.001), lobular hyperplasia (p-value<0.001), calcifications (p-value<0.004), cysts (p-value=0.003), intra-ductal papilloma (p-value=0.005), sclerosing adenosis (p-value=0.002), columnar alterations (p-value<0.001) and radial scar (p-value=0.001) were associated with subsequent breast cancer. Fibroadenomas were inversely associated with subsequent breast cancer (p-value<0.001). In multivariable model after backwards selection, presence of columnar alterations was associated with increased risk of breast cancer, (RR=1.57, 95% CI: 1.16, 2.13). Combining the 9 BBD features associated with subsequent breast cancer in univariate analysis, those with a busy breast score of 5+ was associated with 2.5 times increased risk compared to those with none of these features (RR=2.52, 95% CI: 1.41, 4.49). As a continuous variable for busy breast score, each additional feature conferred a 20% increase in risk of breast cancer (RR=1.20, 95% CI: 1.10, 1.31). Conclusions: Columnar alterations confer increased risk of breast cancer beyond the risks associated with atypical hyperplasia, as does the presence of multiple types of BBD lesions in a single biopsy. These estimates may help improve the current risk assessment models for African American women and highlight the need for additional research regarding the utility of closer surveillance and potentially chemoprevention for reduction of breast cancer in these women. Citation Format: Michele L. Cote, Wei Chen, Julie J. Ruterbusch, Eman Abdulfatah, Visakha Pardeshi, Asra N. Shaik, Marcel T. Ghanim, MHD Fayez Daaboul, Daniel W. Visscher, Sudeshna Bandyopadhyay, Rouba Ali-Fehmi. Benign breast disease and subsequent breast cancer risk: The Detroit cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A25.

Abstract Introduction: The majority of the 1.6 million breast biopsies performed annually in the United States are benign; however, several breast cancer risk models consider a benign biopsy a factor that increases risk of subsequent breast cancer. Fibroadenomas (FA), benign tumors of epithelial and stromal tissue, occur frequently in premenopausal women and more frequently in African American (AA) women than European American (EA) women. A small increased risk of subsequent breast cancer due to FA has been reported in some studies of EA women. We sought to investigate whether the risk of this lesion differs for AA women. Methods: Benign breast biopsies from 3895 AA women diagnosed between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including FA, ductal ectasia, fibrosis, apocrine metaplasia, ductal hyperplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and columnar alterations. These features were also used to categorize FA into simple and complex FA, where complex FA occurs when FA is accompanied by at least one of the following features: cysts, calcifications, apocrine metaplasia or intraductal papilloma. Women were followed for subsequent breast cancer using the Detroit Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between FA and other benign lesions were examined using chi-square tests. Risk of breast cancer was estimated by relative risk ratios and 95% confidence intervals calculated using logistic regression. All models were adjusted for age at biopsy and additionally adjusted for presence of proliferative disease with or without atypia. Results: Of the 3895 AA women, 46.5% presented with FA on biopsy. FA occurred more frequently in biopsies of younger women (p-value < 0.001) and were less likely to include the other benign lesions assessed (all p-value < 0.001). Of the 210 identified breast cancers that developed in this cohort, 72 cancers developed in women with FA on biopsy. FA were associated with a reduction in risk of breast cancer after adjusting for age at biopsy (RR=0.64, 95% CI: 0.48, 0.86) compared to women without FA on biopsy. Reduction in risk was somewhat attenuated when analysis was adjusted for proliferative disease with or without atypia (RR = 0.67, 95%CI: 0.48, 0.936). Similar associations were seen with simple FA (RR =0.61, 95% CI: 0.35, 1.01) and complex FA (RR =0.70, 95% 0.35, 1.01) after adjustment for age at biopsy and proliferative disease with or without atypia. Conclusions: FA are negatively associated with other benign breast disease features. Risk of breast cancer may be reduced in women with FA compared to women with other types of benign lesions. These findings have important implications for modeling breast cancer risk particularly among AA women for whom FAs are common. Citation Format: Asra N. Shaik, Julie J. Ruterbusch, Eman Abdulfatah, Marcel T. Ghanim, MHD Fayez Daaboul, Visakha Pardeshi, Rouba Ali-Fehmi, Daniel W. Visscher, Sudeshna Bandyopadhyay, Michele L. Cote. Fibroadenomas on benign breast biopsy and subsequent breast cancer risk in an African American cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A16.

Abstract An estimated 1.6 million breast biopsies are performed annually in the United States, and the vast majority are benign. Benign breast disease is an established breast cancer risk factor for both Caucasian and African American women. Yet little is still known about benign breast tissue from African American women, who suffer from disproportionately high-grade tumors and poorer breast cancer survival. To better characterize the risk of breast cancer among African American women with benign breast disease, we assessed benign breast disease pathology of African American women in our metropolitan Detroit cohort (n = 3,737). We classified benign breast lesions for pathological characteristics and used logistic regression to estimate subsequent breast cancer risk with histological characteristics. We observed that women whose biopsies showed columnar alterations, columnar cell lesions of the breast, were 1.78-fold more likely to develop an invasive breast cancer [odds ratio (OR) 1.78, 95% confidence interval (CI) 1.19-2.65] after adjusting for age at biopsy, biopsy year, and overall impression. Columnar alterations were not found to be significantly associated with risk of developing ductal carcinoma in situ (DCIS) among African American women [OR 1.53, 95% CI 0.83-2.82]. Next, to identify molecular markers associated with columnar alterations in benign breast lesions, we performed gene expression analyses on biopsy tissues from 27 African American women that subsequently developed an invasive breast cancer. Transcriptional profiling of these lesions identified differentially expressed genes significantly associated with columnar alterations, including ankyrin repeat domain 30A (ANKRD30A). ANKRD30A, also known as NY-BR-1, is a mammary tissue-specific differentiation antigen that is overexpressed in breast cancers. Increased expression of ANKRD30A in benign breast lesions with columnar alterations may be indicative of subsequent breast cancer development. Taken together, novel molecular markers, including ANKRD30A, and ethnicity can lead to better risk assessment and earlier diagnosis of breast cancer. Citation Format: Andreana N. Holowatyj, Rouba Ali-Fehmi, Julie J. Ruterbusch, Eman Abdulfatah, Vishakha Pardeshi, Woodlyne Roquiz, Baraa Alosh, Sudeshna Bandyopadhyay, Derek Radisky, Michele L. Cote. Ankyrin repeat domain 30A as a novel molecular marker of columnar alterations in benign breast disease and subsequent breast cancer in African American women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-378.

Abstract Introduction: Benign breast disease (BBD) is an established risk factor for developing breast cancer, and certain pathologic features in benign breast tissue are more strongly associated with breast cancer risk. Most of the studies evaluating BBD and breast cancer risk have been done in primarily white populations. Our previous work among African American (AA) women with BBD suggested the presence of cysts was associated with increased breast cancer risk. This finding may be unique to AA women as other studies among white populations have not replicated these findings. We sought to further explore the association between breast cysts and breast cancer risk in our expanded AA BBD cohort. Methods: Biopsies from AA women initially diagnosed with BBD from 1997 to 2009 were examined for 14 pathologic features, including the microscopic presence of cysts, and followed for subsequent breast cancer. The association between cysts and the other pathologic features were compared using chi-square tests, and the risk of developing breast cancer was estimated using logistic regression and summarized with odds ratios (OR) and 95% confidence intervals (95% CI). Results: A total of 3,360 AA women with BBD have been identified and their benign biopsies reviewed. 190 women have developed a subsequent breast cancer with a mean follow-up time of 11.5 years. Cysts were present on 1,366 (38%) of the biopsies, and were significantly associated with nearly all of the other benign features evaluated: apocrine metaplasia, ductal hyperplasia, calcifications, duct ectasia, fibrodenomas, fibrosis, intra-ductal papillomas, sclerosing adenosis, columnar alterations, mucocelle-like lesions, radial scars, and proliferation with and without atypia (all p<0.001). Adjusting for age and year of biopsy, cysts were associated with a 36% increase in breast cancer risk (OR: 1.36, 95% CI 1.01 - 1.82). When further adjusted for hyperplasia with atypia, the benign feature with the most established and strongest association with breast cancer risk, the risk associated with cysts was attenuated (OR: 1.20, 95% CI 0.88 - 1.64). Conclusion: Among AA women, cysts are highly correlated with other BBD features that increase subsequent breast cancer risk, but the risk associated with cysts does not appear to be independent of hyperplasia with atypia. Understanding the etiology of BBD and cyst development may provide insight into breast tumorigenesis, and the interplay between cysts and other BBD features warrant further investigation. Citation Format: Julie J. Ruterbusch, Michele L. Cote, Sudeshna Bandyopadhyay, Baraa Alosh, Eman Abdulfatah, Vishakha Pardeshi, Woodlyne Roquiz, Daniel Visscher, Rouba Ali-Fehmi. Presence of cysts in benign breast tissue and the risk of subsequent breast cancer in African American women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1769.